Acyl derivatives and process



United States CERTAIN NITRO IMIDAZOLEALKANOLS AND ACYL DERIVATIVES ANDPROCESS Robert Michel Jacob, Ablon-sur-Seine, Gilbert Louis Regnier,Paris, and Come! Crisan, Sceaux, France, assignors to Societe des UsinesChimiques Rhone- Poulenc, Paris, France, a French body corporate NoDrawing. Filed Jan. 8, 1959, Ser. No. 785,577 Claims priority,application France Sept. 20, 19-57 8 Claims. (Cl. 260- 309) ethyl), Arepresents a divalent saturated straight or branched chain aliphatichydrocarbon group containing two to four carbon atoms and X represents ahydrogen atom or an acyl residue of a monocarboxylic or dicarboxylicaliphatic or aromatic acid, and acid addition salts thereof.

Since large numbers of monocarboxylic and dicarboxylic aliphatic andaromatic acids are known it is impossible to list them exhaustively. Thegeneral utility of acids in these classes is however exemplified by theexamples which follow wherein the ester groupings are selected over aWide range of such acids, e.g. lower aliphatic monocarboxylic acids suchas acetic acid and dichloroacetic acid, higher aliphatic monocarboxylicacids such as pivalic acid and stearic acid, aliphatic dicarboxylicacids such as succinic acid, aromatic monocarboxylic acids such asbenzoic acid and its substitution derivatives such as salicylic acid,chlorobenzoic acids, methoxy benzoic acids and nitrohenzoic acids, andaromatic dicarboxylic acids, of which the phthalic acids are the mostreadily available examples.

According to a feature of the present invention, compounds of theaforesaid general formula in which X is a hydrogen atom, are prepared byreacting in the absence of a basic condensing agent a 4(or5)-nitroimidazole with a compound of the general formula Z-A-OY whereinZ represents an acid residue of a reactive ester selected from a halogenatom and the acid residues of sulphuric and sulphonic esters, Yrepresents a hydrogen atom or a radical which is readily replaceable bya hydrogen atom, for example a tetrahydropyranyl or benzyl group, and Ais as hereinbefore defined and, where Y is other than a hydrogen atom,liberating the hydroxyl group by known methods, e.g. by acid hydrolysiswhen Y is tetrahydropyranyl or benzyl.

According to a further feature of the present inven- -tion, compounds ofthe aforesaid general formula in which X is an acyl group, are preparedflom the corre- "ice spending alcohols (X=H) by known methods ofesterification, in particular, by the action of an acid chloride in thepresence of pyridine.

By the words known methods as used in this specification andaccompanying claims is meant methods heretofore employed or described inthe chemical literature.

The imidazole derivatives of the aforesaid formula possess valuablechemotherapeutic properties; in particular, they have utility in thetreatment of infections due to pathogenic protozoa such as certainspecies of amoebae (for example Endamoeba histolytica) or trichomonas(for example Trichomonas vaginalis). They have a very low toxicity.

For therapeutic purposes, the new imidazoles are preferably employed assuch or in the form of acid addition salts containing anions which arerelatively innocuous to the animal organism in therapeutic doses of thesalts (such as hydrochlorides and other hydrohalides, phosphates,nitrates, sulphates, maleates, fumarates, citrates, tartrates,methanesulphonates and ethanedisulphonates) so that the beneficialphysiological properties inherent in the bases are not vitiated byside-effects ascribable to the anions.

The following examples illustrate the invention.

Example I 2-met-hyl-4(or 5)-nitroimidazole 127 g.) is heated withethylene chlorohydrin (795 g.) for 18 hours at 128- 130" C. and thechlorohydrin (660 g.) is then distilled under reduced pressure (30 mm.Hg). The residue is treated with water (300 cc.) and filtered, and thefiltrate is made alkaline by the addition of sodium hydroxide solution(d=l.33, cc.). It is then extracted with chloroform (1,000 cc.) and,after evaporation of the chloroform in vacuo, there is obtained a pastymass (77 g.) which is recrystallised from ethyl acetate (450 co.) in thepresence of animal charcoal. There is thus obtainedl-(2-hydroxyethyl)-2-methyl-5-nitroimidazole (24 'g.) as a creamy whitecrystalline powder melting at Example II 2-methyl-4(or 5)-nitroimidazole(12.7 g.) and 3-benzyl oxypropyl toluene-p-sulphonate (32 g.) (M.P. 33C.) are heated for 2 hours at 135 C. When the reaction is complete, thereaction mixture is cooled to 25 C. and then "agitated with hydrochloricacid (50 cc.). The 3- benzyloxypropyl toluene-p-sulphonate which has notreacted is extracted with ether and the acid liquors are made alkalinewith potassium carbonate.

The suspension obtained is filtered to remove unreacted 2-methyl4(or5)-nitroimidazole starting material which is washed several times withwater and then with chloroform. The filtrate is then decanted andextracted with chloroform. The chloroformic extracts are combined, driedover anhydrous potassium carbonate and then evaporated under reducedpressure. A crude oily product (22 g.) is obtained.

The crude product is dissolved in 15% hydrochloric acid cc.) anddebenzylation is effected by heating this solution for 5 hours underreflux. After cooling, the solution is extracted several times withchloroform and the acid liquors are then made alkaline with potassiumcarbonate. They are then extracted several times with chloroform and thechloroformic solutions are dried over anhydrous-potassium carbonate.After evaporation of the solvent under reduced pressure a crude oilybase (7 g.) is obtained.

By the addition of ethereal hydrogen chloride to a solution of the basein acetone followed by recrystallisation from a mixture of ethanol andether of the crystals obtained, there is finally obtained1-(3-hydroxypropyl)-2- methyl-S-nitroimidazole hydrochloride (4 g.),M.P. 115 C.

Example III 2-ethyl-4(or 5)-nitroimidazole (23.8 g.) and benzyloxyethyltoluene-p-sulphonate (51.7 g.) (M.P. 43 C.) are heated for 3 hours at135 C; After treatment of the reaction products as in Example I a crudeoily product (26.2 g.) is obtained which is debenzylated by boiling inhydrochloric acid (130 cc.). On treatment of the hydrochloric acidsolution a crude crystalline base (8.2 g.) is obtained which is purifiedby recrystallisation from a mixture of ethyl acetate and heptane. Thereis finally isolated 1-(2-hydroxyethyl)-2-ethyl-5-nitroimidazole (7.25g.), 8788 C. v 7

Example IV 1-( Z-hydroxyethyl) -2-methyl-5-nitroirnidazole 8.55 g.)

'is suspended in anhydrous chloroform (100 cc.). An-

hydrous pyridine (4.15 g.) i.s' added and, after cooling to 5 C.,dichloroacetyl chloride (7.75 g.) isadded dropwi'se over minutes. Whenthe addition is complete, the temperature is allowed to rise to 15 C.and the mixture is then boiled for 1 hour. The chloroform solution isthen cooled and washed several times with water. i After evaporation ofthe solvent the crude ester obtained is purified bysuccessiverecrystallisations from a mixture of benzene and heptane and then fromdi-isopropyl ether. i a i I There is finally obtainedl-(Z-dichloroacetoxyethyl) -2- methyl-S -nitroimidazole (7.2 g.), M.P.8687 C.

Example V ester (14.5 'g.) is obtained which is purified by successiverecrystallisations from petroleum ether. There is finally obtained 1-Z-ste aroyloxyethyl) -2-methyl-5 -nitroimidazole (6.1 g.),M.P. 51 0.

Example VII Proceeding as in Example IV but commencing with l-(2-hydroxyethyl)-2-methyl-5-nitroimidazole (8.5 5 g.) anhydrous pyridine(4.15 g.) dissolved in anhydrous'chloroform (100 cc.) and cinnamoylchloride (8.75 g.), a crude ester (10.9 g.) is obtained, which ispurified by successive recrystallisations from a mixture of ethylacetate and heptane and from di-isopropyl ether. There is finallyobtained I-(Z-cinnamoyloxyethyl) 2=methyl-5- nitroimidazole (6.7 g.),M.P. 100 C.

Example VIII 1(2-hydroxyethyl)-2-methyl-5-nitroimidazole (8.55 g.)issuspended in anhydrous chloroform (100' cc.). Anhydrous pyridine (4.15g.) is added and, after cooling to 5 C., salicyloyl chloride (8.4 g.) isadded dropwise over 50 minutes, the temperature being, kept below 5 C. 7After the addition the temperature is kept at 5 C.

for l hour and the mixture is then agitated at room temperature for 19hours. Water (60 cc.) is then added 4 to the solution and a whiteprecipitate is formed which is separated and some of the initial1-(2-hydroxyethyl)- 2-methyl-5-nitroimidazole is thus recovered. Thefiltrate is decanted and the chloroform solutions are. washed severaltimes with water and then with a 10% solution of sodium bicarbonate.After drying the chloroform solution over anhydrous sodium sulphate andevaporating the solvent, a crude oily base (9.7 g.) is obtained. Afterdissolving the latter in benzene and repeatedly extracting the solutionwith 15% hydrochloric acid, the acid fractions are combined and madealkaline with potassium carbonate. Theyare then extracted several timeswith chloroform andthe combined chloroformic solutions are'dried overanhydrous sodium sulphate. After evaporation of the solvent, the crudebase obtained is purified by dissolving it in ethanol and addingethereal hydrogen chloride. There is finally obtainedI-(Z-salicyloyloxyethyl) -2-methyl-5 -nitroimidazole hydrochloride, M.P.154 C. M

. Example IX 14.7 g. of benzoyl chloride dissolved in 30 cc. of

chloroform are poured into a'cold solution of 17.1 g.

of 1-(2-hydroxyethyl)-2-n1ethyl-5-nitroimidazole in 200" cc. ofchloroform, and 8.3 g. of pyridine are added so that the temperatureremains in the neighbourhood-of 5 .C. The'mixture is then agitated for 1hour atroom temperature, cc. of water are added and the insoluble matteris filtered ed. The organic layer is decanted and washed with 50 cc. ofa 10% sodium bicarbonate solu' tion and then with 100 cc. of water.driven off on the water bath and there are obtained 21 g. of a whitecrystalline residue, which is recrystallised from cyclohexane. There arethus obtained 15 g. of 1-(2- benzoyloxyethyl) -2-methyl-5nitroimidazole,which is a. white crystalline powder, M.P. 100 C.

Example ,X

Into a solution of 17.1 g. of 1-(2-hydroxyethyl) -2-methyl-S-nitroimidazole and 8.3 g. of pyridine in 200 cc. of chloroformis poured a solution of 18.4 g. of o-chlorobenzoyl chloride in 70 cc. ofchloroform, the temperature being maintained below 5 C. during theaddition. The mixture is then agitated for 1 hour in the cold and thenallowed to return to room temperature. 100 cc. of iced Water are thenpoured in, an insoluble fraction is filtered off, and the organic layeris washed with 40 cc. of aqueous 10% sodium bicarbonate solution andthen with 100 cc. of water. The solvent is driven off on a water bathunder reduced. pressure (30 mm. Hg), and the residue is recrystallisedfrom cyclohexane. There are thus obtained 14.8 g. of1-(Z-o-chlorobenzoyloxyethyl) -2-methy1- 5 -nitroimidazole, which is awhite crystalline powder, M.P. 104 C. r

' Example XI .Into a solution of 17.1 g. of 1-(2-hydroxyethyl)-2methyl-S-nitroimidazole and 8.3 g. of pyridine in 200 cc. of chloroformis poured a solution of 22.2 g. of 324:5- trimethoxybenzoyl chloride in70 cc. of chloroform, the temperature being maintained at 23 C. Themixture is thereafter agitated for 1 hour in the cold and then allowedto return to room temperature. 100 cc. of iced water are added and theinsoluble matter is filtered oflf. The organic layer is washed with 40cc. of 10% sodium bicarbonate solution and then with 100 cc. of water.The solvent is driven off on a water bath under reduced pressure (30 mm.Hg). There is obtained a pale yellow oil, which is dissolved in amixture of 40 cc. of chlororam and40 cc. of diethyl ether. 20 cc. of a3.5 N solution of hydrochloric acid in diethyl other are added. The

hydrochloride precipitate is separated off and redissolved inz200 cc. ofchloroform and treated with an excess of solid sodium bicarbonate. Thechloroform solution is filtered and the chloroform is driven olf on awater bath The solvent is Example XII 100 cc. of iced water are run in,the insol canted and washed with 40 cc. of 10% sodium bicarbonatesolution and then with 100 cc. of water. The solvent is driven off onthe water bath under reduced pressure (30 mm. Hg), and there remains ayellow oil (24 -g.). The oil obtained is dissolved in 50 cc. of diethylether and 100 cc. of chloroform, and 50 cc. of a 3.5 N solution ofhydrochloric acid in diethyl ether are added. The hydrochlorideprecipitate obtained is suction-filtered and washed with 50 cc. ofchloroform and 50 cc. of ether. It is thereafter re-suspended in 200 cc.of chloroform and there are added 30 g. of solid sodium bicarbonate.After the reaction, the chloroform solution is filtered off, theprecipitate is washed with 50 cc. of chloroform and the solvent isdriven off on the water bath under reduced pressure (300 mm. Hg). Thewhite residue weighing 19 g. is recrystallised from a mixture ofcyclohexane and benzene. There are thus obtained 16.9 g. of1-(2-p-methoxy-benzoyloxyethyl)-2-methyl-5-nitroimidazole, which is awhite crystalline powder, M.P. 102 C.

Example XIII Into a solution of 17 .1 g. of 1-(2-hydroxyethyl)-2-methyl-S-nitroimidazole and 8.3 g. of pyridine in 200 cc. of chloroformare run 20.2 g. of p-nitrobenzoyl chloride in 90 cc. of chloroform, thetemperature remaining at 4 C. The mixture is agitated for 1 hour in iceand then allowed to return to room temperature. 100 cc. of iced waterare added and a considerable quantity of insoluble matter (A) isfiltered oif. The chloroform solution is washed with 40 cc. of a 10%sodium bicarbonate solution and then with 100 cc. of water. Thechloroform is driven off on a water bath and a crystalline residue (B)is obtained.

The products (A) and (B) are combined and dissolved in 150 cc. ofchloroform. 0.4 g. of pyridine are added to the suspension obtained, 0.9g. of p-nitrobenzoyl chloride are run in and the mixture is agitated forhours at ambient temperature. The product is diluted with 100 cc. ofchloroform and washed with 40 cc. of a 10% sodium bicarbonate solutionand then with 100 cc. of water. After drying over sodium sulphate, thechloroform is driven off on the water bath under reduced pressure (30mm. Hg). There remains a pale yellow solid (10 g.), which isrecrystallised from ethyl acetate, whereby there are obtained 7 g. of1-(2-p-nitrobenzoyloxyethyl)- 2-methyl-5-nitroimidazole, which is a paleyellow crystalline powder, M.P. 166 C.

Example XIV Into a solution of 17.1 g. of1-(2-hydroxyethyl)-2-methyl-S-nitroimidazole and 8.3 g. of pyridine in250 cc. of chloroform are poured 12.6 g. of pivalyl chloride in 50 cc.of chloroform, the temperature being maintained at 3-4 C. The mixture isthereafter allowed to return to room temperature and is then refluxedfor 1 hour. After cooling, 50 cc. of iced water are added, the insolublematter is filtered off and the organic layer is decanted and washed with40 cc. of a 10% sodium bicarbonate solution and then with 60 cc. ofwater. The chloroform is driven off on the water bath under reducedpressure (300 mm. Hg) and there are obtained 14 g. of a brownishgreenoil. The oil is taken up in 100 cc. of ether and 30 cc. of a 3.5 Nsolution of hydrochloric. acid in diethyl ether are added. Theprecipitate is filtered off and washed with 45 cc. of ether. It is thentaken up in 300 cc. of chloroform and the insoluble matter is filteredoff. To the solution are added 65 g. of powdered sodium bicarbonate, theinsoluble matter is filtered off, the solvent is driven off on a waterbath and the residue is recrystallised from petroleum spirit. There arethus obtained which is a white crystalline powder, M.P. 39 g i ExampleXV Into a 'solution of 17.1 g. of I-(Z-hydroxyethyl)-2-methyl-5-nitroimidazole and 8.3 g. of pyridine in 150 cc. ofchloroform are poured 11 g. of phthalyl chloride dis solved in 50 cc. ofchloroform, the temperature remaining below 3 C. during the addition.The temperature is maintained at 10-15 C. for 3 hours, cc. of iced waterare added, the insoluble fraction is filtered off, and the chloroformlayer is washed with 15 cc. of a 10% sodium bicarbonate solution andthen with 100 cc. of water. The chloroform is driven off on the waterbath under reduced pressure (30 mm. Hg). There remains a brown oil whichis crystallised from 100 cc. of diethyl ether. After recrystallisationfrom ethyl acetate, there are obtained 7 g. of the neutral phthalicester of 1-(2- hydroxyethyl)-2-methyl-5-nitroimidazole, which is a whitecrystalline powder, M.P. C.

Example XVI Into a solution of 17.1 g. of I-(Z-hydroxyethyD-Z-methyl-S-nitroimidazole and 8.3 g. of pyridine in 200 cc. of chloroformare poured 8.1 g. of succinyl chloride in 30 cc. of chloroform, thetemperature remaining below 5 C. The mixture is allowed to return to theambient temperature and agitated for 1 hour. 100 cc. of iced water areadded, the insoluble matter is filtered off and the chloroform layer isdecanted and washed with 50 cc. of a 10% sodium bicarbonate solution andthen with 60 cc. of water. The chloroform is driven ofi on a water bathunder reduced pressure (30 mm. Hg.) and the gummy residue isrecrystallised from cc. of benzene. There are thus obtained 9 g. of theneutral succinic ester of 1-(2-hydroxyethyl) -2-methyl-5-nitroimidazole,which is a white crystalline powder, M.P. 128 C.

We claim:

1. A member of the class consisting of an imidazole derivative of thegeneral formula:

HC-N

A-OX

wherein R represents a member of the class consisting of a hydrogen atomand an alkyl group containing up to five carbon atoms, A represents asaturated aliphatic wholly hydrocarbon group containing two to fourcarbon atoms and X is a member of the class consisting of N-alkanoicacyl containing 1-17 carbon atoms in the alkane radical, dichloroacetyl,pivaloyl, cinnamoyl, succinoyl, benzoyl, chlorobenzoyl, methoxybenzoyl,nitrobenzoyl, salicyloyl, phthaloyl, acid addition salts of the abovemembers having pharmaceutically acceptable anions and hydrogen.

2. The compound 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole.

3. The compound 1-(2-benzoyloxyethyl)-2-methyl-5- nitroimidazole.

4. The compound 1-(2-succinoyloxyethyl)-2-methyl-5- nitroimidazole.

5. The compound 1-(2-hydroxyethy1)-2-ethyl-5-nitroimidazole.

6. The compound 1-(2-cinnamoyloxyethyl)-2-methyl- S-nitroimidazole.

pound of ghej general formula; s'

wherein represents arnember of the class consistingof 1 I V r Y 7 and Yis selected from the class consisting of a hydrogen a hydrogen atom andan alkyl group containing up to five carbon atoms, andA represents asaturated aliphatic whollyhydrocarbon group containing two to fourcarbon atoms which'vcomprises reacting iIl'ihe absence of a basiccondensing agent 3. 4(01 5)-nitroimidazo1e with a 15 a m goal 8 compoundof the general formula Z-AOY wherein Z is selected from the classconsisting of C1- and atomand benzyl and, where Y is benzyl, liberatingthe, hydroxyl' group by acid hydrolysis.

No references cited.

Lib

1. A MEMBER OF THE CLASS CONSISTING OF AN IMIDAZOLE DERIVATIVE OF THEGENERAL FORMULA: